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Here, by integrating ovariectomy (OVX)\u2010induced osteoporosis models, osteoblast\u2010specific\n                    <jats:italic>Sting<\/jats:italic>\n                    knockout mice, and staged in\u00a0vitro osteoclastogenesis models, we report that STING temporally regulates osteoclast differentiation without participating in osteoblast\u2010mediated bone homeostasis. Through the timed administration of the STING inhibitor C\u2010176, we found a non\u2010monotonic bone response to STING inhibition in OVX mice. Early intervention was found to significantly increase bone mass, while therapeutic efficacy progressively decreased in later stages, with intervention at the terminal stage exacerbating bone loss. Furthermore, osteoblast\u2010specific\n                    <jats:italic>Sting<\/jats:italic>\n                    knockout mice showed no change in bone mass whether in the static state or after OVX. In\u00a0vitro assays revealed that the STING downstream temporal partitioning of nuclear factor kappa\u2010B (NF\u2010\u03baB) and interferon (IFN) pathways bidirectionally dictated osteoclast differentiation. Activation of the NF\u2010\u03baB pathway drove cell fate commitment, whereas activation of the IFN pathway inhibited multinuclear maturation. Moreover, polymerase chain reaction array and transcriptomic analyses supported the stage\u2010specific activation of NF\u2010\u03baB and IFN pathways during both human and murine osteoclastogenesis. Collectively, these findings establish a critical early therapeutic window for STING inhibition and highlight a timed strategy to maximize osteoprotective efficacy while avoiding adverse outcomes in osteoporosis.\n                  <\/jats:p>","DOI":"10.1096\/fj.202502905rr","type":"journal-article","created":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T10:29:02Z","timestamp":1773484142000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Osteoclastogenesis Responds to\n                    <scp>STING<\/scp>\n                    Inhibition in a Non\u2010Monotonic Manner"],"prefix":"10.1096","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-7186-385X","authenticated-orcid":false,"given":"Liangjie","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Orthopedics, Xijing Hospital Fourth Military Medical University  Xi'an China"},{"name":"Department of Orthopedics No. 954 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